Mass spectrometry analysis techniques are generally carried out under conditions of high vacuum. However, various types of ion sources used to generate ions for MS analyses operate at or near atmospheric pressures. Thus, those skilled in the art are continually confronted with challenges associated with transporting ions and other charged particles generated at atmospheric or near atmospheric pressures, and in many cases contained within a large gas flow, into regions maintained under high vacuum.
Most mass spectrometers with an Atmospheric Pressure Ion (API) source are equipped with a small bore capillary (often referred to as an “ion transfer tube”) to limit gas conductance for good vacuum inside the instrument and proper functioning of the mass analyzer. But limiting gas conductance also severely restricts ion sampling from the API source into the mass spectrometer and limits the overall sensitivity of the mass spectrometer (Bruins, A. P., “Mass spectrometry with ion sources operating at atmospheric pressure”, Mass Spectrom. Rev., 1991, 10(1), pp. 53-77). One approach that has been employed to alleviate the restriction has been to increase the conductance of the capillary (frequently by increasing the capillary diameter, D) so as to allow more ions into the mass spectrometer. Unfortunately, an increase in the conductance can render the vacuum inside the mass spectrometer unsuitable for mass analysis. This result is implied in the Hagen-Poiseuille derivation that relates conductance to a capillary D as described below:
                    C        =                  180          ⁢                      (                                          D                4                            L                        )                    ⁢                                    P              av                        .                                              Eq        .                                  ⁢        1            where the length, L, is in centimeters and the average pressure (Pav) is in Torr (Moore, J. H.; Davis, C. C.; and Coplan, M. A., Building Scientific Instruments, 4th ed.; Cambridge University Press: New York, USA, 2009). The dependence of C on the fourth power of the diameter, D, implies that a subtle increase in conductance will yield excessive gas load for the vacuum pumps. This has been a developmental bottleneck that defines, in part, the sensitivity of a mass spectrometer. Efforts over the last decade have trended towards increasing the inlet gas throughput, Q, and developing ways to handle the complications that arise from high Q, such as increasing vacuum pumping capacity.
Various approaches have been proposed in the mass spectrometry art for improving ion transport efficiency into low vacuum regions. For example, FIGS. 1A-1B are two schematic depictions of mass spectrometer systems 1-2 which utilize an ion transport apparatus to so as to deliver ions generated at near atmospheric pressure to a mass analyzer operating under high vacuum conditions. As one example, analyte ions may be formed by the electrospray (ESI) technique by introducing a sample comprising a plume 9 of charged ions and droplets into an ionization chamber 7. In the illustrated example, ions are generated via an electrospray needle 10. For an ion source that utilizes the electrospray technique, ionization chamber 7 will generally be maintained at or near atmospheric pressure. Although an electrospray ion source is illustrated, the ion source may comprise any other conventional continuous or pulsed atmospheric pressure ion source, such as a thermal spray source, an APCI source or a MALDI source.
In the systems 1-2 illustrated in FIGS. 1A-1B, the analyte ions, together with background gas and possibly partially desolvated droplets, flow into the inlet end of a conventional ion transfer tube 15 (e.g., a narrow-bore capillary tube) and traverse the length of the tube under the influence of a pressure gradient. Analyte ion transfer tube 15 is preferably held in good thermal contact with a heating block 12. The analyte ions emerge from the outlet end of ion transfer tube 15, which opens to an entrance 27 of an ion transport device 5 located within a first low vacuum chamber 13. As indicated by the arrow on vacuum port 31, chamber 13 is evacuated to a low vacuum pressure by, for example, a mechanical pump or equivalent. Under typical operating conditions, the pressure within the low vacuum chamber 13 will be in the range of 1-10 Torr (approximately 1-10 millibar), but it is believed that the ion transport device 5 may be successfully operated over a broad range of low vacuum and near-atmospheric pressures, e.g., between 0.1 millibar and 1 bar.
After being constricted into a narrow beam by the ion transport device 5, the ions are directed through aperture 22 of extraction lens 14 so as to exit the first low pressure chamber 13 and enter into an ion accumulator 36, which is likewise evacuated, but to a lower pressure than the pressure in the first low pressure chamber 13, also by a second vacuum port 35. The ion accumulator 36 functions to accumulate ions derived from the ions generated by ion source 10. The ion accumulator 36 can be, for example, in the form of a multipole ion guide, such as an RF quadrupole ion trap or a RF linear multipole ion trap. Where ion accumulator 36 is an RF quadrupole ion trap, the range and efficiency of the ion mass-to-charge ratios captured in the RF quadrupole ion trap may be controlled by, for example, selecting the RF and DC voltages used to generate the quadrupole field, or applying supplementary fields, e.g. broadband waveforms. A collision or damping gas such as helium, nitrogen, or argon, for example, can be introduced via inlet 23 into the ion accumulator 36. The neutral gas provides for stabilization of the ions accumulated in the ion accumulator and can provide target molecules for collisions with ions so as to cause collision-induced fragmentation of the ions, when desired.
The ion accumulator 36 may be configured to radially eject the accumulated ions towards an ion detector 37, which is electronically coupled to an associated electronics/processing unit 24. The ion accumulator 36 may alternatively be configured to eject ions axially so as to be detected by ion detector 34. The detector 37 (or detector 34) detects the ejected ions. Sample detector 37 (or detector 34) can be any conventional detector that can be used to detect ions ejected from ion accumulator 36.
Ion accumulator 36 may also be configured, as shown in FIG. 1B, to eject ions axially towards a subsequent mass analyzer 45 through aperture 28 (optionally passing through ion transfer optics which are not shown) where the ions can be analyzed. The ions are detected by the ion detector 47 and its associated electronics/processing unit 44. The mass analyzer 45 may comprise an RF quadrupole ion trap mass analyzer, a Fourier-transform ion cyclotron resonance (FT-ICR) mass analyzer, an Orbitrap™ electrostatic-trap type mass analyzer or other type of electrostatic trap mass analyzer or a time-of-flight (TOF) mass analyzer. If the mass analyzer 45 is an Orbitrap™ electrostatic-trap type mass analyzer, then the ions ejected from the accumulator 36 may be ejected radially to the mass analyzer instead of axially. The analyzer is housed within a high vacuum chamber 46 that is evacuated by vacuum port 43. In alternative configurations, ions that are ejected axially from the ion accumulator 36 may be detected directly by an ion detector (47) within the high vacuum chamber 46. As one non-limiting example, the mass analyzer 45 may comprise a quadrupole mass filter which is operated so as to transmit ions that are axially ejected from the ion accumulator 36 through to the detector 47.
FIGS. 1A-1B illustrate two particular examples of mass spectrometer systems in which ion transport devices may be used to deliver ions from an atmospheric or near-atmospheric ion source into a vacuum chamber. Such ion transport devices may be of various types including, for example, the ion transport device illustrated in FIG. 2A, the well-known ion funnel devices (discussed further in the following in reference to FIG. 3), the ion transport apparatuses disclosed herein and discussed below in reference to FIGS. 5A-5C, 6, 7 and 8A as well as other types. All these ion transport devices may be generally employed in other types of mass spectrometer systems in addition to the systems shown in FIGS. 1A-1B. For example, whereas the systems of FIGS. 1A-1B include an ion accumulator or ion trap (36), other mass spectrometer systems, such as triple-quadrupole mass spectrometer systems, may similarly advantageously employ such ion transport devices (as are known in the art or as described in the present teachings). Instead of employing an ion accumulator or ion trap mass analyzer, triple quadrupole systems (not specifically illustrated in the drawings) instead generally employ a sequence of quadrupole apparatuses comprising: a quadrupole mass filter (Q1), an RF-only quadrupole collision cell (Q2) and a second quadrupole mass filter (Q3). As with the systems illustrated in FIGS. 1A-1B, these mass analyzer components reside in one or more evacuated chambers and, thus, an ion transport apparatus and system as disclosed herein may be advantageously employed if ions are generated in an atmospheric or near-atmospheric ion source.
FIG. 2A depicts (in rough cross-sectional view) details of an example of an ion transport device 5 as taught in U.S. Pat. No. 7,781,728, which is assigned to the assignee of the instant invention and is hereby incorporated by reference herein in its entirety. Ion transport device 5 is formed from a plurality of generally planar electrodes 38, comprising a set of first electrodes 16 and a set of second electrodes 20, arranged in longitudinally spaced-apart relation (as used herein, the term “longitudinally” denotes the axis defined by the overall movement of ions along ion channel 32). Devices of this general construction are sometimes referred to in the mass spectrometry art as “stacked-ring” ion guides. An individual electrode 38 is illustrated in FIG. 2B. FIG. 2B illustrates that each electrode 38 is adapted with an aperture 33 through which ions may pass. The apertures collectively define an ion channel 32 (see FIG. 2A), which may be straight or curved, depending on the lateral alignment of the apertures. To improve manufacturability and reduce cost, all of the electrodes 38 may have identically sized apertures 33. An oscillatory (e.g., radio-frequency) voltage source 42 applies oscillatory voltages to electrodes 38 to thereby generate a field that radially confines ions within the ion channel 32. Preferably, each electrode 38 receives an oscillatory voltage that is equal in amplitude and frequency but opposite in phase to the oscillatory voltage applied to the adjacent electrodes. As depicted, electrodes 38 may be divided into a plurality of first electrodes 16 interleaved with a plurality of second electrodes 20, with the first electrodes 16 receiving an oscillatory voltage that is opposite in phase with respect to the oscillatory voltage applied to the second electrodes 20. In this regard, note that the first electrodes 16 and the second electrodes 20 are respectively electrically connected to opposite terminals of the oscillatory voltage source 42. In a typical implementation, the frequency and amplitude of the applied oscillatory voltages are 0.5-3 MHz and 50-400 Vp-p (peak-to-peak), the required amplitude being strongly dependent on frequency.
To create a tapered electric field that focuses the ions to a narrow beam proximate the exit 39 of the ion transport device 5, the longitudinal spacing of electrodes 38 may increase in the direction of ion travel. It is known in the art (see, e.g., U.S. Pat. No. 5,572,035 to Franzen) that the radial penetration of an oscillatory field in a stacked ring ion guide is proportional to the inter-electrode spacing. Near entrance 27, electrodes 38 are relatively closely spaced, which provides limited radial field penetration, thereby producing a wide field-free region around the longitudinal axis. This condition promotes high efficiency of acceptance of ions flowing from the ion transfer tube 15 into the ion channel 32. Furthermore, the close spacing of electrodes near entrance 27 produces a strongly reflective surface and shallow pseudo-potential wells that do not trap ions of a diffuse ion cloud. In contrast, electrodes 38 positioned near exit 39 are relatively widely spaced, which provides effective focusing of ions (due to the greater radial oscillatory field penetration and narrowing of the field-free region) to the central longitudinal axis. A longitudinal DC field may be created within the ion channel 32 by providing a DC voltage source 41 that applies a set of DC voltages to electrodes 38.
In an alternative embodiment of an ion transport device, the electrodes may be regularly spaced along the longitudinal axis. To generate the tapered radial field, in such an alternative embodiment, that promotes high ion acceptance efficiency at the entrance of the ion transport device as well as tight focusing of the ion beam at the device exit, the amplitude of oscillatory voltages applied to electrodes increases in the direction of ion travel.
A second known ion transport apparatus is described in U.S. Pat. No. 6,107,628 to Smith et al. and is conventionally known as an “ion funnel”. FIG. 3 provides a schematic depiction of such an ion funnel apparatus 50 in both a longitudinal cross-sectional view and end-on view as viewed along the axis 51. Roughly described, the ion funnel device consists of a multitude of closely longitudinally spaced ring electrodes, such as the four illustrated ring electrodes 52a-52d, that have apertures that decrease in size from the entrance of the device to its exit. In FIG. 3 as well as in subsequent drawings, different patterns on the representations of the various different electrodes are provided only to aid in visual distinguishing between the various electrode representations and are not intended to imply that the electrodes are necessarily formed of differing materials. The apertures are defined by the ring inner surfaces 53 and the ion entrance corresponds with the largest aperture 54, and the ion exit corresponds with the smallest aperture 55. The electrodes are electrically isolated from each other, for example, by insulator boards 57, and radio-frequency (RF) voltages are applied to the electrodes in a prescribed phase relationship to radially confine the ions to the interior of the device.
The relatively large aperture size at the entrance of the ion funnel apparatus (FIG. 3) provides for a large ion acceptance area, and the progressively reduced aperture size creates a “tapered” RF field having a field free zone that decreases in diameter along the direction of ion travel, thereby focusing ions to a narrow beam which may then be passed through the aperture of a skimmer or other electrostatic lens without incurring a large degree of ion losses. Generally, an RF voltage is applied to each of the successive ring elements so that the RF voltages of each successive element are 180 degrees out of phase with the adjacent element(s). A direct current (DC) electrical field may be created using a power supply and a resistor chain (not illustrated) to supply the desired and sufficient voltage to each element to create the desired net motion of ions down the funnel. The electrical connections to the ring electrodes as well as ancillary electronic components, such as voltage dividing resistors may be provided on the insulator boards 57 in the form of conventional printed circuits. Still further, the ring electrodes themselves may be printed components of the insulator boards 57. The boards (printed circuit substrates) may be fabricated from conventional printed circuit board material such as a cloth or fiber material—such as cotton or woven glass fibers—that is impregnated with a resin—such as epoxy.
The depiction in FIG. 3 of the ion funnel known in the art is very schematic. Practical implementations of this device often include a first portion of the device that has a plurality of spaced-apart ring electrodes 52a all having the same large inner diameter and a second portion of the device having the ring electrodes 52a-52d, etc. whose inner diameters taper down gradually so as to focus the ions towards the central axis and the smallest orifice at the exit end 55. The first portion is located on the side where the ions enter the device. In operation, the ion-laden gas emerging from the atmospheric pressure enters, by means of one or more orifices or, in the example shown, an ion transfer tube 15, into a first portion of the device where it emerges at high velocity and undergoes rapid gas expansion. The length of the first portion of the device provides a minimum lateral distance between the ion transfer tube 15 (or other entrance orifice or orifices or multiple ion transfer tubes) and the tapering-diameter second portion within which the forward velocity of the ion laden gas is lowered by collisions with background gas. When the forward velocity of the ion laden gas has sufficiently been lowered, it becomes possible to manipulate the ions with radio frequency electric fields with low enough amplitudes to be below the Paschen breakdown limit, and preferentially guide the ions towards the exit end 55. Refinements to and variations on the ion funnel device are described in (for example) U.S. Pat. No. 6,583,408 to Smith et al., U.S. Pat. No. 7,064,321 to Franzen, EP App. No. 1,465,234 to Bruker Daltonics, and Julian et al., “Ion Funnels for the Masses: Experiments and Simulations with a Simplified Ion Funnel”, J. Amer. Soc. Mass Spec., vol. 16, pp. 1708-1712 (2005).
As noted in the foregoing discussion, various conventional mass spectrometer system designs use an ion transfer tube to transport solvent laden cluster ions and gas into a first vacuum chamber of a mass spectrometer where either an ion funnel or a stacked ring ion guide used to capture the ion cloud from the free jet expansion. As the high velocity gas enters the ion funnel or stacked ring ion guide, ions are propelled by the co-expanding gas predominantly in the forward direction and are controlled and guided by the RF field towards a central orifice at the exit end of the ion funnel or stacked ring ion guide. The inventors have observed that, as the high velocity gas impacts solid components of such ion transport apparatuses, it leaves a distinctive mark comprising a residue of contaminants that build up on certain portions of the electrodes. Over time, the continued build up of these deposited contaminants can cause electrical arcing across the closely spaced electrodes and can change the electrical permittivity of ion lenses, which in turn reduces ion transmission. As a result, mass spectrometers that employ such ion transport devices require occasional time-consuming disassembly and cleaning of these devices. The disassembly and cleaning steps caused by the impingement of gas onto the electrodes may be complicated by the presence of insulator boards 57 and their associated wires or other electronic components
The robustness of ion optics has been a key factor in stimulating efforts to improve the atmospheric-vacuum interface of mass spectrometers. Earlier designs have trended towards enlarging the circular inner diameter of a mass spectrometer gas inlet (e.g., an ion transfer tube) to allow more ions into the mass spectrometer. However, the above-noted problem of deposition of neutrals on electrodes can be exacerbated when ion transfer tubes are simply increased in inner diameter in this fashion. Conventionally, the impact of this on instrument robustness has been minimized by maintaining adequate desolvation of ions across the ion transfer tube and evacuating the increased gas load.
The ion transfer tube (or capillary) 15 represents a major restriction in the flow of ions from an atmospheric pressure ion source and into a mass spectrometer. The progressive step down in pressure across multiple mass spectrometer chambers (pumping stages), as depicted in FIGS. 1A-1B and described above is vital for the proper functioning of ion optics in each chamber and for maintaining transport of ions across the multiple pumping stages. However, attempts to increase the ion flux into the mass spectrometer by increasing the bore size of the ion transfer tube that transports ions from the ionization chamber to the first low vacuum chamber is often complicated by two key issues:
1.) Firstly, more gas will flow from the atmosphere into the mass spectrometer, which will increase the pressures in each of the downstream pumping stages. At some point, the pressures can exceed those essential for the proper functioning of the radio frequency (RF) ion guides in each chamber causing a poor radial confinement and axial propulsion of ions towards the detector.
2.) Secondly, increasing the inner diameter of the capillary bore will reduce the amount of heat transfer from the body of the capillary to the flow stream. This contributes to poor de-solvation, depressed analyte response, and elevated chemical noise.
One common practice to overcome the two limitations involve increasing the number of pumping stages to gradually remove the excess gas load and increasing the capillary temperature to facilitate more heat transfer. However, signal losses caused by the additional pumping stage (or stages) and increases in chemical noise due to poor de-solvation have made such practice difficult and costly.
FIG. 4 is a schematic illustration of a portion, in particular, an outlet portion of a known ion transfer tube 15. The upper and lower parts of FIG. 4 respectively show a cross-sectional view and a perspective view of the outlet portion of the ion transfer tube 15. The ion transfer tube comprises a tube member 152 (in this example, a cylindrical tube) having a hollow cylindrical interior or bore 154, the flow direction through which is indicated by the dashed arrow. At the outlet end 151 of the ion transfer tube, the tube member 152 is terminated by a substantially flat end surface 156 that is substantially perpendicular to the length of the tube and to the flow direction. Further, a beveled surface or chamfer 158, which in the case of the cylindrical tube shown is a frustoconical surface, may be disposed at an angle to the end surface so as to intersect both the end surface 156 and the outer cylindrical surface of the tube member 152. The surface 158 may be used to align and seat the outlet end of the ion transfer tube against a mating structural element (not shown) in the interior of the intermediate vacuum chamber 13 or may be used so as to penetrate, upon insertion into a mass spectrometer instrument, a vacuum sealing element or valve, such as the sealing ball disclosed in U.S. Pat. No. 6,667,474, in the names of Abramson et al.
The number of ions delivered to the mass analyzer (as measured by peak intensities or total ion count) is partially governed by the flow rate through the ion transfer tube. One of the ways to increase the sensitivity of a mass spectrometer is to let in more ion laden-gas from the ionization chamber 7, provided that enough vacuum pumping is being applied to maintain a sufficient level of vacuum in the mass spectrometer for it to function. Unfortunately, the practice of offsetting the increased gas load of a wider bore ion transfer tube by increasing pumping capacity or the number of pumping stages (i.e., intermediate-vacuum chambers) so as to maintain a functional vacuum inside the mass spectrometer is generally seen as complicated and costly. Further, the approach of increasing the throughput of the conventional round-bore ion transfer tube 15, either by shortening it or increasing its inner diameter, has been found experimentally to be limited by how well the solvent surrounding the ions can be evaporated during the transfer time of the tube. The ion transfer tube may be heated to improve solvent evaporation and ion de-solvation. However, the maximum temperature that can be applied to the ion transfer tube is limited due to melting of nearby plastic parts as well as to fragmentation of fragile molecular ions such as certain peptides that may flow through the tube.
Traditionally ion funnels or stacked ring ion guides are constructed from a stack of parallel plates (metal or metalized around the orifice of an FR-4 printed circuit board), each plate having an orifice. In the case of ion funnels, the orifices are of decreasing diameter in the direction from the apparatus entrance to the apparatus exit. The outside edges of the plates are generally of quasi constant dimensions, shaped, for example, circularly, square, or some combination thereof. In some designs, also solid spacers are inserted between the plates to keep them apart.
As a result of this multiple parallel plate construction, high velocity gas from the expansion out of the ion transfer tube cannot easily escape the ion transport apparatus so that it can be pumped away. Consequently, gas pressure may increase to an undesirable level in the chamber containing the ion transport device. The internal pressure increase may be especially serious in the case of ion-funnel-type ion transport apparatuses, since the projection of the funnel along its symmetry axis shows or presents only the orifice at the end as an opening for escaping gas. The conductance between successive funnel electrodes is oriented close to perpendicular to the direction of the expansion, which creates a relatively high pressure area in the funnel. This has negatively affected the ion transmission efficiency of the ion funnel or stacked ring ion guide and, although operation at higher RF frequencies can help to alleviate this problem, reducing the pressure within the device itself is a better solution if one wants to keep increasing the throughput from the atmospheric pressure ionization source. In addition, the robustness of the device (as measured by the useful operational time between necessary cleanings) is limited by the beam impacting on the electrodes opposite the transfer tube.